JP2019518058A - Solid state form of spiro-oxindole compounds - Google Patents

Abstract

The present invention relates to solid state forms of certain spiro-oxindole compounds such as funapide and a racemic mixture of funapide and its corresponding (R) enantiomer, pharmaceutical compositions comprising these solid state forms and Provided are processes for preparing solid state forms and pharmaceutical compositions. The present invention is directed to the preparation of pharmaceutical compositions of spiro-oxindole compounds, any one of the specific spiro-oxindole compounds disclosed herein, preferably in the solid state form of funapide or racemic mixture. Including use.

Description

FIELD OF THE INVENTION The present invention relates to solid state forms of certain spiro-oxindole compounds, pharmaceutical compositions comprising these solid state forms and pharmaceutically acceptable additives, and solid state forms and pharmaceutical compositions thereof. Include a process for preparing a product.

BACKGROUND OF THE INVENTION PCT published patent application WO 2006/110917, PCT published patent application WO 2010/045251, PCT published patent application WO 2010/045197, PCT published patent application WO 2011/047174, PCT published patent application WO 2011 / WO No. 0027 08, PCT Published Patent Application WO 2011/106729 and PCT Published Patent Application WO 2013/154712 include certain spiro-oxindole compounds, methods of preparing spiro-oxindole compounds, spiro-oxindole compounds Disclosed are pharmaceutical compositions and / or methods of using spiro-oxindole compounds.

を有し、その化学名は（Ｓ）−１’−｛［５−（トリフルオロメチル）フラン−２−イル］メチル｝スピロ［フロ［２，３−ｆ］［１，３］ベンゾジオキソール−７，３’−インドール］−２’（１’Ｈ）−オンである。 One of these spiro-oxindole compounds is funapide, also known as TV-45070 or XEN402. Funapide is represented by the following formula (I-S):

And its chemical name is (S) -1 '-{[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodiox Sole-7,3'-indole] -2 '(1'H) -one.

  In particular, PCT published patent application WO 2011/020708 specifically discloses funapide and its corresponding (R) -enantiomer. PCT Published Patent Application No. WO 2011/047174 discloses a method for preparing funapide by resolving racemic form of funapide by SMB chromatography or chiral HPLC. Also, PCT Published Patent Application No. WO 2013/154712 discloses a method for preparing funapide by asymmetric synthesis.

  Funapide is the (S) -enantiomer of the racemic compound previously disclosed as compound # 428 in PCT published patent application WO 2006/110917. Compound # 428 is also known as XEN401.

  Pharmaceutical compositions comprising funapide and funapide are sodium channel mediated diseases, preferably pain related diseases, central nervous pathologies such as epilepsy, anxiety, depression and bipolar disease; arrhythmias, atrial fibrillation and ventricular fibrillation Cardiovascular conditions such as; neuromuscular conditions such as restless leg syndrome; neuroprotection from stroke, nerve trauma and multiple sclerosis; and useful in treating channel disease such as cutaneous red pain and familial rectal pain syndrome is there.

  The relevant disclosure content of the above published patent application is incorporated herein by reference in its entirety.

Polymorphism, which is the presence of different crystalline forms of the same molecule, is a property of some molecules and molecular complexes. Single molecules have well-defined crystal structures as well as melting points, thermal behavior (e.g. measured by differential scanning calorimetry "DSC" or thermogravimetric analysis "TGA"), X-ray diffraction patterns, infrared absorption fingerprints, and solid state ^{(13 C-)} may be formed various polymorphs having distinct physical properties, such as NMR spectra. One or more of these techniques can be used to identify different polymorphic forms of a compound.

  Different solid state forms (including solvated forms) of the active ingredient may have different characteristics. Such differences in the properties of the different solid state forms and solvates may, for example, facilitate the improvement of processing or handling characteristics, change the dissolution profile in a preferred direction, or stability (polymorphic stability and chemical stability Improved shelf life and shelf life can provide the basis for improved formulations. These differences in the properties of the different solid state forms may also lead to an improvement in the final dosage form, for example when serving to improve the bioavailability. Different solid state forms and solvates of the active ingredient may result in different polymorphs or crystalline forms, which in turn assess differences in the properties and characteristics of the active ingredient of the solid. Provide additional opportunities for

  By discovering novel solid state forms and solvates of pharmaceutical products, materials with desirable processing properties such as ease of handling, ease of processing, storage stability, and ease of purification, or Materials can be obtained as crystalline forms of the desired intermediate that facilitate conversion to other polymorphic forms. Novel solid state forms of pharmaceutically useful compounds can also provide the opportunity to improve the performance characteristics of pharmaceutical products. It has, for example, different properties, such as different crystal habits, higher crystallinity or polymorphic stability which can lead to better processing or handling characteristics, improved dissolution profiles, or improved shelf life (chemical / physical To extend the repertoire of materials that formulation scientists can use for formulation optimization by providing products with For at least these reasons, a solid state form of funapide (including solvated forms) is needed.

WO 2006/110917 WO 2010/045251 WO 2010/045197 International Publication No. 2011/0174174 International Publication No. 2011/020708 International Publication No. 2011/106729 WO 2013/154712

SUMMARY OF THE INVENTION The present invention provides solid state forms of certain spiro-oxindole compounds disclosed herein, preferably funapide or racemic mixtures, and pharmaceutical compositions thereof.
The present invention is directed to the preparation of pharmaceutical compositions of spiro-oxindole compounds, any one of the specific spiro-oxindole compounds disclosed herein, preferably in the solid state form of funapide or racemic mixture. Including use.

  The present invention also provides methods of preparing solid state forms of certain spiro-oxindole compounds disclosed herein, preferably funapide or racemic mixtures.

  The invention also provides a process for preparing the pharmaceutical composition as described above. The process combines the specific spiro-oxindole compounds disclosed herein, preferably any one of the solid state forms of funapide or racemic mixture, with at least one pharmaceutically acceptable additive. Including.

  Solid-state forms and pharmaceutical compositions of certain spiro-oxindole compounds, preferably funapide or racemic mixtures, can be used as medicaments, in particular for the treatment of sodium channel-mediated diseases and conditions such as pain. .

  The present invention is a method of treating sodium channel-mediated diseases and conditions, such as pain, comprising a therapeutically effective amount of a solid of a particular spiro-oxindole compound disclosed herein, preferably a funapide or racemic mixture. Administering any one of the status forms, or at least one of the pharmaceutical compositions described above, to a subject suffering from sodium channel-mediated diseases and conditions, such as pain or otherwise in need of treatment Also provides a method.

FIG. 1 shows the characteristic powder X-ray diffractogram of form A ₀ of funapide (TV-45070).

FIG. 2 shows a DSC thermograph of Form A ₀ of Funapide (XEN-402).

FIG. 3 shows an ATR FTIR spectrum of form A ₀ of funapide.

FIG. 4 shows the Raman shift spectrum of form A ₀ of funapide.

FIG. 5 shows the characteristic powder X-ray diffractogram of form B ₀ of funapide (TV-45070).

FIG. 6 shows a DSC thermograph of Form B ₀ of funapide (TV-45070).

FIG. 7 shows an ATR FTIR spectrum of form B ₀ of funapide.

FIG. 8 shows the Raman shift spectrum of form B ₀ of funapide.

FIG. 9 shows the characteristic powder X-ray diffractogram of amorphous funapide (TV-45070).

FIG. 10 shows an amorphous DSC thermograph of funapide (TV-45070).

FIG. 11 shows a characteristic powder X-ray diffractogram of a racemic mixture of funapide and its corresponding (R) -enantiomer.

FIG. 12 shows the Raman shift spectrum of a racemic mixture of funapide and its corresponding (R) -enantiomer.

FIG. 13 shows an overlay of the powder x-ray diffractogram of the racemic mixture, form A ₀ of funapide and form B ₀ of funapide.

FIG. 14 shows an overlay of the Raman shift spectra of the racemic mixture, Form A ₀ and Form B ₀ .

Detailed Description of the Invention The present invention includes solid state forms of the specific spiro-oxindole compounds, preferably of funapide or of the racemic mixture of funapide and its corresponding (R) -enantiomer. The solid state properties of the funapide or racemic mixture can be influenced by control of the conditions under which the funapide or racemic mixture is obtained in solid form.

  As used herein, “a solid state form of a particular spiro-oxindole compound” refers to the crystalline form of funapide described herein, the amorphous form of funapide, and funapide and its corresponding (R) -enantiomer It is intended to include crystalline forms of racemic mixtures, including:

  In some embodiments, the crystalline forms of funapide of the present invention are substantially free of any other form of funapide or a designated polymorphic form of funapide, respectively.

  As used herein, “substantially free” when referring to the solid state form of funapide is that the solid state form of the present invention is 20% by weight or less of any other polymorph or designated of funapide. It is intended to be meant to contain the polymorphic form, or the amorphous form of funapide. According to some embodiments, the solid state form of funapide is 10% by weight or less, 5% by weight or less, 2% by weight or less, 1% by weight or less, 0.5% by weight or It contains less than or 0.2% by weight or less of any other polymorph or specified polymorph of funapide, or the amorphous form of funapide. In other embodiments, the solid state form of funapid of the present invention comprises 1% to 20%, 5% to 20%, or 5% to 10% by weight of funapide in any other solid state form. Or contains the designated polymorphic form, or the amorphous form of funapide.

  Depending on the other solid state forms to be compared, the crystalline form of the funapide of the invention has advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology Or crystallographic stability in relation to polymorphic conversion and stability such as thermal and mechanical stability, stability against dehydration and / or storage stability, low content residual solvent, lower moisture absorption, flow Properties and advantageous processing and handling characteristics such as compressibility and bulk density.

  In particular, it has been found that the crystal form of the funapide of the present invention is very soluble in a number of solvents such as acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran and toluene. The crystalline form of funapide according to the invention also exhibits good physical stability.

  As used herein, the term "very soluble" with respect to the solid state form of funapide according to the invention corresponds to the solid state form of funapide having a solubility of more than 100 mg / mL at room temperature.

  Solid state forms, such as crystalline or amorphous forms, may be referred to herein as being characterized by the data of the graphs "shown in" or "substantially shown". Such data include, for example, powder X-ray diffractograms, DSC thermographs, FTIR spectra by ATR and Raman shift spectra. As is well known in the art, the data of the graph may be additional technical information (so-called "" to further define each solid state form that can not be described by referring to the numerical value or peak position alone. Potentially provide "fingerprint"). In any event, those skilled in the art will appreciate that such graphical representations of the data are due to particular factors such as (but not limited to) differences in instrument response and differences in sample concentration and purity that are well known to those skilled in the art. It is understood that small relative differences in peak relative intensity and peak position, for example, may be prone to occur. Nevertheless, one skilled in the art can easily compare the data of the graphs in the figures herein with the data of graphs generated for unknown crystal forms, and the data of the two sets of graphs show the same crystal form It can be confirmed whether it has the feature of or the feature of two different crystal forms. Thus, the crystal form of the funapide or racemic mixture, which is referred to herein as characterized by the data of the graphs “shown in” or “substantially shown” in comparison with the figures It is considered to include any crystal form of the funapide or racemic mixture characterized by the data of such small difference graphs well known to the person skilled in the art.

  As used herein, the term "isolated" with respect to the solid state form of the funapid or racemic mixture of the present invention corresponds to the solid state form of funapide or racemic mixture physically separated from the reaction mixture formed. .

  Herein, unless otherwise stated, XRPD measurements are performed using copper Kα radiation at 45 kV and 40 mA.

  As used herein, unless otherwise stated, DSC measurements were taken with a thermal gradient of 10 ° C./min.

  An object or mixture, such as a solid state form of funapide or a racemic mixture or a reaction mixture or solution, as referred to herein, is or is "room temperature" or "ambient temperature" (often abbreviated as "RT") It is intended to mean that the temperature of the object or mixture is close to or the same as the temperature of the space in which the object or mixture is located, such as a room or draft chamber, when characterized as being able to . Typically, the room temperature is about 20 ° C. to about 30 ° C., or about 22 ° C. to about 27 ° C., or about 25 ° C.

  The amount of solvent used in a chemical process, such as reaction or crystallization, may be referred to herein as a numerical value "volume" or "vol" or "V". For example, the material can be said to be suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression should be understood to mean milliliters of solvent per gram of material suspended, thus suspending 5 grams of material in 10 volumes of solvent Means that the solvent is used in an amount of 10 milliliters of solvent per gram of material suspended or, in this example, 50 mL of solvent. In another context, the term "v / v" can be used to indicate the number of volumes of solvent added to the liquid mixture relative to the volume of the liquid mixture. For example, adding solvent X (1.5 v / v) to 100 ml of reaction mixture would indicate that 150 mL of solvent X was added.

  A process or step may be referred to herein as being performed "overnight". This refers to the time interval of the process or step over the nighttime time, for example, where the process or step may not be actively observed. This time interval is about 8 to about 20 hours, or about 10 to 18 hours, typically about 16 hours.

  As used herein, the term "reduced pressure" refers to a pressure that is less than atmospheric pressure. For example, the reduced pressure is about 10 mbar to about 50 mbar.

As used herein, "crystal form A _{0 of} funapide" or "form A ₀ " or "form A _{0 of} funapide" is a crystal form of funapide which can be characterized by the powder X-ray diffraction pattern shown in FIG. Point to

As used herein, "crystalline form B ₀ of Funapido" or "Form B _0" or "Form B ₀ of Funapido" is a crystalline form of Funapido which can be characterized by powder X-ray diffraction pattern shown in Figure 5 Point to

  As used herein, “amorphous form of funapide” has a powder X-ray diffraction pattern as shown in FIG. 9, and further a DSC thermograph as shown in FIG. 10 which exhibits a glass transition temperature of 42 ° C. and a crystallization temperature of 72 ° C. Refers to the amorphous form of funapide that can be characterized by

  As used herein, "racemic mixture" refers to a crystalline form of a racemic mixture of funapide and its corresponding (R) -enantiomer, which can be characterized by the powder X-ray diffraction pattern shown in FIG.

In one embodiment, the present invention includes a crystalline form of the following, characterized by data selected from one or more of, it referred to as crystalline form A ₀ of Funapido herein Funapido: 10.10 ° Powder X-ray diffraction patterns having peaks at 10.69 °, 20.59 °, 22.69 ° and 33.12 ° θ ± 0.2 ° θ; powder X-ray diffraction pattern shown in FIG. 1; As well as the combination of these data.

The crystal form A ₀ of funapide has peaks at 10.10 °, 10.69 °, 20.59 °, 22.69 ° and 33.12 ° θ ± 0.2 ° θ, and further 15.94 ° Powder X also having an additional one, two, three or four peaks selected from: 17.77 °, 20.26 °, 23.79 ° and 30.84 ° θ ± 0.2 ° θ Line diffraction pattern; DSC thermogram shown in FIG. 2; melting point 110-116 ° C., preferably melting point 114-116 ° C .; FTIR spectrum shown in FIG. 3; and Raman shift spectrum shown in FIG. Can be further characterized by

The crystal form A _{0 of} funapide is, for example, 10.10 °, 10.69 °, 20.59 °, 22.69 ° and 33.12 ° θ, depending on each and every conceivable combination of the above-mentioned features. It can be characterized by the powder X-ray diffraction pattern having a peak at ± 0.2 ° θ as well as the powder X-ray diffraction pattern shown in FIG.

In another embodiment, the crystal form A _{0 of} funapide is characterized by one or more of the following Raman shift peaks listed in Table 1:

In another embodiment, the present invention includes a crystalline form of Funapido termed crystal form B ₀ of Funapido herein characterized by data selected from one or more of the following: 9.61 ° Powder X-ray diffraction patterns having peaks at 10.03 °, 14.95 °, 19.28 ° and 21.30 ° θ ± 0.2 ° θ; powder X-ray diffraction pattern shown in FIG. 5; As well as the combination of these data.

The crystal form B _{0 of} funapide has peaks at 9.61 °, 10.03 °, 14.95 °, 19.28 ° and 21.30 ° θ ± 0.2 ° θ, and 12.51 °, Powder X-ray with additional one, two, three or four peaks selected from 16.14 °, 18.03 °, 18.72 ° and 25.50 ° θ ± 0.2 ° θ Diffraction patterns can be further characterized by the DSC thermogram shown in FIG. 6 showing a melting point of 104-107 ° C .; the FTIR spectrum shown in FIG. 7 as well as the Raman shift spectrum shown in FIG.

The crystal form B _{0 of} funapide is, for example, 9.61 °, 10.03 °, 14.95 °, 19.28 ° and 21.30 ° θ depending on each and every conceivable combination of the above-mentioned features. It can be characterized by the powder X-ray diffraction pattern having a peak at ± 0.2 ° θ as well as the powder X-ray diffraction pattern shown in FIG.

In another embodiment, the crystalline form B ₀ of Funapido is characterized by one or more of the following Raman shifts peaks listed in Table 2.

  In one embodiment, the present invention is characterized by the data selected from one or more of the following: Funapide, referred to herein as a crystalline form of the racemic mixture, and its corresponding (R) -enantiomer Powder form of the racemic mixture: powder X-ray diffraction pattern with peaks at 13.68 °, 14.83 °, 20.17 °, 25.49 ° and 29.80 ° θ ± 0.2 ° θ; 11. Powder X-ray diffraction pattern shown in 11; as well as combinations of these data.

  The crystalline form of the racemic mixture has peaks at 13.68 °, 14.83 °, 20.17 °, 25.49 ° and 29.80 ° θ ± 0.2 ° θ, 15.94 °, 22 A powder X-ray diffraction pattern also having an additional one, two, three or four peaks selected from .24 °, 27.21 ° and 31.91 ° θ ± 0.2 ° θ; It can be further characterized by the Raman shift spectrum shown in.

In another embodiment, the racemic mixture is characterized by one or more of the XRPD peaks listed in Table 3.

In another embodiment, the crystalline form of the racemic mixture is characterized by one or more of the following Raman shift peaks listed in Table 4:

  The present invention includes pharmaceutical compositions and formulations comprising the crystalline form of funapide of the present invention, any one of the crystalline form of funapide or a crystalline form of racemic mixture, and one or more additives. Typically, the pharmaceutical composition is a solid composition, in which the funapide retains its solid state form.

  The pharmaceutical composition of the present invention may be prepared by the same method as disclosed in PCT published patent application WO 2011/0174174, or by the same method as disclosed in PCT published patent application WO 2013/154712, or PCT published patent application It can be prepared in a manner similar to that disclosed in application WO 2011/106729.

  The above crystal forms of the funapide and racemic mixture of the present invention as well as the amorphous form of funapide can also be used as medicaments.

  The invention relates to 1) the use of the above crystalline or amorphous or racemic mixture of the forms of funapide in the preparation of a pharmaceutical composition, and 2) sodium channel mediated diseases and conditions such as pain or otherwise A method of treating a subject in need of treatment, the administration of an effective amount of a pharmaceutical composition comprising any one of the above crystalline or amorphous forms of funapide described herein The method further includes.

  The crystalline form of funapide or the crystalline form of the above amorphous form or racemic mixture, and the use of a pharmaceutical composition comprising the same, in treating the diseases and conditions described in PCT published patent application WO2011 / 0202078. It can be used.

  Having thus described the invention with reference to preferred specific embodiments and specific examples, those skilled in the art will appreciate the spirit and scope of the invention disclosed herein to the invention described and illustrated. It is possible to understand modifications that do not deviate from the scope. The examples are set forth to aid in understanding the invention but are in no way limiting on the scope of the invention and should not be construed as limiting the scope of the invention.

  The funapide used herein to prepare the crystalline form of funapide disclosed herein can be used according to the method disclosed in PCT published patent application WO2011 / 047174 and / or PCT published patent application WO2013 It was prepared by the method disclosed in US / 154712.

Analytical method XRPD-Powder X-ray diffraction X-ray powder diffraction (Powder (Powder) on a PANalytical X'Pert Pro diffractometer equipped with an X'celerator detector, using Cu Kα radiation at 45 kV and 40 mA The XRPD pattern, also known as powder X-ray diffraction or powder XRD, was recorded. The diffractometer was controlled using a PANalytical Data Collector1. All samples were analyzed using the algorithm on HighScore Plus2.

Standard reflection mode Kα1 rays were obtained using a highly oriented crystal (Ge 111) incident beam monochromator. A 10 mm beam mask and fixed (1/4 °) divergence and anti-scatter (1/8 °) slits were inserted on the incident beam side. A 0.04 radian Soller slit and a 5 mm fixed light receiving slit were inserted on the diffracted beam side. Collection of powder X-ray pattern scans was performed at about 2-40 ° 2θ, step size 0.0080 °, and counting time 96.06 seconds, resulting in a scan rate of approximately 0.5 ° / min. The samples were spread on a silicon zero background (ZBG) plate for measurement. The sample was spun at 15 rev / min with a PANalytical PW3065 / 12 Spinner. Measurement of the Si reference standard prior to data collection gave values of 2θ and intensity well within the tolerance of 28.0 ° <2θ <28.5 ° and significantly greater than 150 cps of the minimum peak height .

Powder XRD patterns were recorded on a PANalytical X Pert Pro diffractometer equipped with a capillary transmission mode X celerator detector using Cu Kα radiation at 45 kV and 40 mA. An incident beam (Cu W / Si) focusing MPD mirror was used in the incident beam path. Fixed (1/20) divergence and anti-scatter (1/40) slits and 0.01 Soller were inserted on the incident beam side. A 5.0 mm fixed anti-scatter slit and 0.01 Soller were inserted on the diffracted beam side. If using an anti-scatter device (PW 3094/10), place an additional 2.0 mm slit 197 mm from the detector. Collection of powder X-ray pattern scans was performed at approximately 2.75-40 ° 2θ, step size 0.0080 °, and counting time 101 seconds, resulting in a scan rate of approximately 0.5 ° / min. The sample was loaded into a thin walled Kapton capillary and placed in a modified transmission holder. The holder is a standard transmission sample ring with added mechanical features that allow for measurement of the rotating capillary.

Variable Temperature (VT) Mode Variable temperature studies were conducted under computer control using an Anton Paar CHC temperature / humidity chamber. The temperature was set on the data collector using an Anton Paar TCU 110 temperature control unit.

  A K filter was obtained using a nickel filter. Fixed (1/40) divergence and anti-scatter (1/20) slits were inserted on the incident beam side. A fixed light receiving slit of 0.10 mm was inserted on the diffracted beam side. Soller slits (0.04 radians) were inserted on both the incident and diffracted beam sides. Collection of powder X-ray pattern scans was performed at about 2-40 ° 2θ, step size 0.0080 °, and counting time 96.06 seconds, resulting in a scan rate of approximately 0.5 ° / min.

In the temperature studies, measurements were made using a stream of N ₂ gas. The temperature chosen for the study was the temperature based on the DSC results. The measurement was started after the CHC chamber reached the required temperature. After reaching the required temperature, the sample was cooled at 35 ° C./min and a slow scan was measured at 25 ° C. This technique avoids "heating" the sample at higher temperatures. The scan collection was performed at about 3 ° -30 ° or 40 ° 2θ, with a step size of 0.008 ° and a counting time of 100 seconds, resulting in a scan rate of approximately 0.5 ° / min.

DSC-Differential Scanning Calorimetry A Perkin-Elmer Sapphire DSC unit equipped with an autosampler running Pyris software version 6.0 was used to calibrate with indium prior to analysis to obtain a thermal curve. 1 to 10 mg of solid sample was weighed into a 20 μL aluminum pinhole sample pan. The DSC cell was then purged with nitrogen and the temperature was heated at 10 ° C./min from 0 to 270 ° C. Calibrated using indium (Tm = 156.6 ° C .; ΔHFus = 28.45 J / g).

FTIR Spectroscopy Spectra were obtained using a Bruker Tensor 27 with an ATR attachment containing a diamond crystal window. An IR spectrum 4000-400 cm ⁻¹ was obtained using the OPUS data acquisition program (version 7.0, Bruker). Background scans were collected and averaged before spectral resolution.

Raman Spectroscopy Raman spectra were collected on a Vertex 70 FTIR (Bruker) optical bench equipped with a 1064 nm NdYAG laser and a liquid nitrogen cooled Ge detector using a RAMII module or RamanScope. Thirty-two scans were collected with a dual acquisition mode, a scan rate of 5 KHz, and an aperture of 5 mm. Data were processed with phase resolved 32 cm ⁻¹ , 8 × zero fill and weak Norton-Beer apodization functions. Sample spectra were collected through glass vials using RAMII whenever possible. Irregular samples were analyzed using a 10x objective with a Raman Scope. In that situation, 64 scans were collected at 1197 mW laser power.

Screening Methods Slurry Equilibration in Various Solvents Equilibration at 25 ° C. Approximately 20 mg of funapide was equilibrated with about 0.2 mL of solvent at 25 ± 3 ° C. for at least 48 hours in a 4 mL vial. The resulting mixture was filtered and the solid air dried for at least 10 minutes.

Equilibration at 50 ° C. Approximately 40 mg of funapide was equilibrated with about 0.4 mL of solvent at 50 ° C. for at least 24 hours in a 4 mL vial. The solution was then filtered and air dried for at least 10 minutes.

Cooling crystallization at 5 ° C. Approximately 20 mg of funapide was completely dissolved in 200 μL of solvent at 22-25 ° C. in a 4 mL vial. Care was taken to ensure that no visible crystals remained. The solution was cooled to 5 ° C. at a rate of 2 ° C./min. The precipitate (if present) was collected on a filter and dried.

Evaporation Slow evaporation at 5 ° C. Approximately 20 mg of funapide was completely dissolved in 200 μL of solvent at 22-25 ° C. in a 4 mL vial. The solution was cooled to 5 ° C. at a rate of 2 ° C./min. Care was taken to ensure that no visible crystals remained. The solvent was allowed to slowly evaporate for at least 1 day by uncapping each vial while maintaining temperature and agitation.

Fast evaporation at 50 ° C. Approximately 40 mg of funapide was mixed with 200 μL of solvent at 22-25 ° C. in a 4 mL vial. The solution was heated to 50 ° C. as quickly as possible by the instrument. Care was taken to ensure that no visible crystals remained at this point. While maintaining temperature and agitation, the cover of each vial was opened and the solvent was quickly evaporated to dryness.

Precipitation by Antisolvent Addition In a 4 mL vial, approximately 20 mg of funapide was completely dissolved in the solvent with high solubility of funapide, followed by the addition of a second solvent in which the funapide is very insoluble. A sample was taken out of the obtained slurry. The sample was filtered to obtain a solid.

(Examples 1 to 66)
The following Examples 1 to 66 are the solid state forms of funapide obtained by screening in various solvents as described above.

(Example 67)
Crystallization process Funapido form _{B 0} of Funapido the (1.952Kg) was dissolved in methanol (3.62 vol) of 7070ML. A complete solution was obtained at 56 ° C. (in the reactor) in a 10 L reactor. When the reactor temperature reached 64 ° C., 742 mL of water was added dropwise over 65 minutes. At the end of the water addition time, a clean solution was also obtained (reactor temperature reached 68 ° C.). The solution was mixed for 30 minutes. The jacket temperature was cooled to 85-40 ° C. over 40 minutes. At the end of this cooling time, the temperature in the reactor reached 59 ° C. (jacket temperature was 40 ° C.) and a white slurry was obtained. The slurry was cooled to 40 ° C. to −5 ° C. over 5 hours, depending on the reactor jacket temperature, and mixed for an additional 11.5 hours. The resulting solid was collected by filtration and washed with a cold mixture of methanol and water (908 mL of water and 1160 mL of methanol). The white solid was dried in a vacuum oven at 50 ° C. for 43 hours to obtain a dry solid. Yield: 1831 g (93.8% of theory).

The material was analyzed by XRPD and showed a Form B ₀ pattern. The DSC of the sample has a thermal event of 106.6 ° C., consistent with typical Form B ₀ .

(Example 68)
Preparation of Amorphous Form of Funapide A. The amorphous form of funapide was produced by melting the form A ₀ of funapide in a dry N ₂ atmosphere, optionally using a VT stage on an XRPD unit. The sample was heated to 140 ° C., then cooled to room temperature and ground. No degradation was observed. The XRPD confirmed that the sample was in the amorphous form of funapide.

B. Alternatively, Funapide Form B ₀ may be similarly melted to produce the amorphous form of Funapide.

(Example 69)
Solid-State Characterization of Racemic Mixtures Considering a racemic mixture comprising funapide (as form A ₀ of funapide) and its corresponding (R) -enantiomer, whether the racemic mixture is a racemate or a racemic conglomerate It was decided whether there was.

  FIG. 11 shows the characteristic powder X-ray diffractogram of the racemic mixture. FIG. 12 shows the Raman shift spectrum of the racemic mixture.

FIG. 13 shows an overlay of the powder x-ray diffractogram of the racemic mixture, form A ₀ of funapide and form B ₀ of funapide. FIG. 14 shows an overlay of the Raman shift spectra of the racemic mixture, Form A ₀ and Form B ₀ .

The racemic mixture has a dramatically different XRPD pattern and melting point from Form A ₀ and Form B ₀ (110 ° C. for Form A ₀ and 140 ° C. vs. 104 ° C. for Form B ₀ ). The racemic mixture was also more pronounced as compared to Form A ₀ or Form B ₀ with some Raman peak shifts.

In order to identify the nature of the racemic mixture, a binary phase diagram by DSC of the mixture of racemic mixture and Form A ₀ was constructed based on experimental results and theoretical predictions. Good agreement was found between experimental results and theoretical predictions. The typical binary phase diagram of the racemate confirmed that the racemate is a racemate (rather than a racemic conglomerate).

Racemic mixtures, six overlay DSC thermogram of various mixtures of Form A _0, and the racemic mixture and form A ₀ is Form A ₀ and racemic mixtures are both corresponding to the melting of Form A ₀ and racemic mixtures 1 It was shown to have a sharp peak of the book. In a mixture of racemic mixture and Form A ₀ , two endothermic peaks are recognized: eutectic melting (its onset is defined as T _E ) and melting of pure species (whose maximum is defined as T _f ) It was done.

The crystal structure of the racemic mixture was solved. One molecule was present in the asymmetric unit, and four pairs of enantiomers were packed in one unit cell. In addition, the molecule matched the "U-shape" of Form B ₀ (by rotation along the N-CH ₂ bond in funapid a "chair shape" or Form B ₀ matched to Form A ₀ Shape occurs)).

  Crystal structure determination of the racemic mixture provides confirmation that the racemic mixture is a racemate rather than a conglomerate.

  All US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications and non-patent publications mentioned herein are hereby incorporated by reference in their entirety.

  While the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the present invention is not to be limited to the details described herein, and attached. Modifications can be made within the scope of the claims and within the equivalents.

Claims (19)

A crystalline form of funapide, designated as Form A ₀ , having the following peaks: 10.10 °, 10.69 °, 20.59 °, 22.69 ° and 33.12 ° θ ± 0.2 ° θ Powder X-ray diffraction pattern; powder X-ray diffraction pattern substantially as shown in FIG. 1; and crystalline forms characterized by one or more of any combination of these data.   Characterized by a powder X-ray diffraction pattern with peaks at 10.10 °, 10.69 °, 20.59 °, 22.69 ° and 33.12 ° θ ± 0.2 ° θ, 15.94 ° Additional one, two, three, four or five powders X selected from 17.77 °, 20.26 °, 23.79 °, and 30.84 ° θ ± 0.2 ° θ 2. The crystalline form of claim 1 further characterized by a line diffraction pattern peak.   The following: a DSC thermogram substantially as shown in Figure 2; further characterized by one or more of an endothermic onset temperature of 109 ° C and a peak maximum temperature of 114 ° C, or a combination thereof The crystal form according to any one of Items 1 to 2. A crystalline form of funapide termed Form B _0, with the following peaks: 9.61 °, 10.03 °, 14.95 °, 19.28 °, and 21.30 ° θ ± 0.2 ° θ A powder X-ray diffraction pattern having; a powder X-ray diffraction pattern substantially as shown in FIG. 5; and a crystalline form characterized by one or more of any combination of these data.   Characterized by a powder X-ray diffraction pattern with peaks at 9.61 °, 10.03 °, 14.95 °, 19.28 °, and 21.30 ° θ ± 0.2 ° θ, 12.51 ° , 16.14 °, 18.03 °, 18.72 °, and 25.50 ° θ ± 0.2 ° θ additional 1, 2, 3, 4 or 5 powders selected from 5. The crystalline form of claim 4, further characterized by an X-ray diffraction pattern peak.   The following: further characterized by one or more of a DSC thermogram substantially as shown in FIG. 6; endothermic onset temperature 103 ° C. and peak maximum temperature 105 ° C., or a combination thereof The crystal form according to any one of Items 4 to 5.   A crystal form of a racemic mixture of funapide and its corresponding (R) -enantiomer, comprising: 13.68 °, 14.83 °, 20.17 °, 25.49 ° and 29.80 ° θ ± A powder X-ray diffraction pattern with a peak at 0.2 ° θ; a powder X-ray diffraction pattern shown in FIG. 11; and a crystalline form characterized by one or more of combinations of these data.   A pharmaceutical composition comprising a crystal form of funapide according to any of the preceding claims 1 to 6 or a crystal form of a racemic mixture of funapide according to claim 7 and its corresponding (R) -enantiomer.   A crystalline form of funapide according to any of the preceding claims 1 to 6 or a crystalline form of a racemic mixture of funapide according to claim 7 and its corresponding (R) -enantiomer, or according to claim 8 A pharmaceutical composition comprising: and at least one pharmaceutically acceptable additive.   Use of a crystalline form of funapide according to any of the preceding claims 1 to 6 in the manufacture of a pharmaceutical composition or formulation or claim 7 and a corresponding (R) -enantiomer thereof Use of crystalline forms of racemic mixtures.   A crystalline form of funapide according to any of the preceding claims 1 to 6 for use as a medicament, a crystal of a racemic mixture of funapide according to claim 7 and its corresponding (R) -enantiomer Pharmaceutical composition according to the form or claim 8.   A crystalline form of funapide according to any of the preceding claims 1 to 6 for use in the treatment of subjects suffering from sodium channel mediated diseases and conditions such as pain, a funapide according to claim 7 and its correspondence A crystalline form of a racemic mixture of (R) -enantiomers, the pharmaceutical composition according to claim 8, or the pharmaceutical preparation according to claim 9.   A method of treating a subject afflicted with sodium channel mediated diseases and conditions, such as pain, comprising treating a therapeutically effective amount of a crystalline form of funapide according to any of the preceding claims 1 to 6 A method comprising administering a crystalline form of a racemic mixture of funapide of and a corresponding (R) -enantiomer thereof, a pharmaceutical composition according to claim 8 or a pharmaceutical formulation according to claim 9.   A method of preparing a pharmaceutical composition according to the invention, which is a crystalline form of funapide according to any of the preceding claims 1 to 6 or funapide according to claim 7 and its corresponding (R) -mirror image Combining the crystalline form of a racemic mixture of isomers with one or more pharmaceutically acceptable excipients. A method of preparing the crystalline form of funapide referred to as Form A ₀ described herein. A method of preparing the crystalline form of funapide referred to as Form B ₀ described herein.   A method of preparing crystalline forms of a racemic mixture of funapide according to claim 7 and its corresponding (R) -enantiomer.   The amorphous form of funapide characterized by the powder X-ray diffraction pattern shown in FIG. 9 and the DSC thermograph shown in FIG. 10 showing a glass transition temperature of 42 ° C. and a crystallization temperature of 72 ° C. .   Method of preparing the amorphous form of funapide described herein.

Images